Angiogenesis, Metastasis, and the Cellular Microenvironment SDF-1a Induces PDGF-B Expression and the Differentiation of Bone Marrow Cells into Pericytes

Platelet-derived growth factor B (PDGF-B) and its receptor, PDGFR-b, play a critical role in pericyte maturation; however, the mechanisms by which PDGF-B is upregulated in the tumor microenvironment remain unclear. We previously showed that upregulating stromal-derived factor, SDF-1a, in VEGF165-inhibited Ewing's sarcoma tumors (TC/siVEGF7-1) induced PDGF-BmRNA expression, increased infiltration and differentiation of bonemarrow cells (BMC) into pericytes and, rescued tumor growth. The purpose of this studywas to investigate the mechanism by which SDF-1a increased PDGF-B expression and the role of this pathway in BM-derived pericyte differentiation. We showed that SDF-1a induced expression of PDGF-B mRNA and protein both in vitro and in vivo. In contrast, inhibiting SDF-1a downregulated PDGF-B. We cloned the 2-kb pdgf-b promoter fragment and showed that SDF-1a activates PDGF-B via a transcriptionalmechanism.Chromatin immunoprecipitation showed that the ELK-1 transcription factor binds to the pdgf-b promoter in response to SDF-1a. We confirmed the correlation between the SDF-1a/PDGF-B pathway and the differentiation of PDGFR-bþ BMCs into mature pericytes using an in vitro assay. These findings show that SDF-1a regulates PDGF-B expression and that this regulation plays a critical role in the differentiation of PDGFR-bþ BMCs into mature pericytes.Mol Cancer Res; 9(11); 1462–70. 2011 AACR.